Balsalazide disodium is the drug substance of the reference branded drug, COLAZAL®. COLAZAL is indicated for the treatment of gastrointestinal diseases, for example mild to moderately active ulcerative colitis, radiation protosigmoidits, and colon cancer (see WO 95/18622). Balsalazide is a colon-specific, non-steroidal, anti-inflammatory aminosalicylate derivative. Balsalazide is also a prodrug containing 5-ASA, linked to 4-amino benzoyl-β-alanine (“4-ABA”) by a diazo bond. While 5-ASA is the active therapeutic moiety of balsalazide, it is rapidly converted to the metabolite N-acetyl-5-ASA (NASA) in the mucosa (Allgayer H, Ahnfelt N O, Kruis W et al. Gastroenterology. 1989; 97:38-41). Approximately, 12% of the oral dose can be measured in the blood as this metabolite as compared to <2% of the oral dose of 5-ASA that is systemically absorbed (COLAZAL Package Insert, September 2006). NASA is known to be of lower anti-inflammatory activity in the colon (van Hogezand R A, van Hees P A, van Gorp J P, van Lier H J, Bakker J H, Double-blind comparison of 5-aminosalicylic acid and acetyl-5-aminosalicylic acid suppositories in subjects with idiopathic proctitis. Aliment Pharmacol Ther. 1988 February; 2(1):33-40), and is therefore thought to be less toxic when in the systemic circulation.
Pharmacokinetic studies have not previously been conducted to evaluate the effect of food on the pharmacokinetics of balsalazides, e.g., balsalazide. More bioavailability of the drug substance and less systemic adsorption has been sought to increase both speed of onset and amount of therapeutic effect.
Thus, there is a need in the art for dose regimens that decrease the systemic level of total mesalamine (5-ASA and NASA) and increase the systemic level of NASA at the expense of decreasing the level of 5-ASA (e.g., the ratio of NASA to 5-ASA) in the systemic circulation. There is also a need in the art for dose regimens that delay the transit of 5-ASA in the colon, as this will also result in an increase in contact time with the colonic mucosa, and increase efficacy of the drug.